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Highly efficient bimetallic iron-palladium catalyzed Michael-type FriedelЦCrafts reactions of indoles with chalcones.

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Full Paper
Received: 14 September 2008
Revised: 24 October 2008
Accepted: 17 November 2008
Published online in Wiley Interscience: 29 December 2008
(www.interscience.com) DOI 10.1002/aoc.1478
Highly efficient bimetallic iron-palladium
catalyzed Michael-type Friedel–Crafts
reactions of indoles with chalcones
Yue-Hua Gaoa , Lei Yanga , Wei Zhoua , Li-Wen Xua,b∗ and Chun-Gu Xiaa∗
Iron–palladium is a superior bimetallic catalyst in the presence of acetylacetone (Acac) with remarkable synergistic effect for
the Michael-type Friedel–Crafts reactions of indoles with chalcones. This catalytic system has the advantages of mild reaction
conditions, smaller amount of metal salts, high yields of the desired products and operational simplicity, which make it a useful
c 2008 John Wiley & Sons, Ltd.
and promising process for the synthesis of indole derivatives. Copyright Supporting information may be found in the online version of this article.
Keywords: bimetallic catalysis; Lewis acid; Michael addition; Friedel–Crafts Reaction; indoles; chalcones
Introduction
114
The bifunctional, bimetallic catalysts have been applied to various organic transformations in recent
decades,[1 – 3] such as cyanation,[4] Friedel–Crafts acylation,[5]
Friedel–Crafts alkylation,[6 – 8] oxidation,[9] hydroformylation,[10]
allylic etherification,[11] nitro-Mannich reaction[12] and other
rections.[13 – 15] Heterobimetallic catalysts offer superior results
in terms of efficiency and selectivity relative to the individual ones.
Mechanistic studies suggest that the synergistic functions of two
metal active sites make substrates more reactive in the transition
state and control their positions so that the functional groups
are proximal to each other. Moreover, the cooperative effects
also enable transformations that have never been possible using
conventional catalysts employing only Lewis acidity. With our
continuous research in developing novel catalysts in Michael-type
Friedel–Crafts reactions,[16,17] we report the efficient Michael-type
Friedel–Crafts addition of indoles with chalcones catalyzed by an
iron–palladium bimetallic catalytic system.
The development of new efficient, clean and highly selective
synthetic methods of indole derivatives has attracted much
attention because of their important role as versatile building
bocks in the synthesis of biologically active compounds and natural
products.[18,19] Since the 3-position of indole is the preferred site
for the electrophilic substitution reaction, the introduction of
functionalized alkyl frameworks at this position by means of a
Friedel–Crafts reaction involving the use of various electrophilic
reagents constitutes a well-established strategy. Among the
Friedel–Crafts reactions, the Michael-type Friedel–Crafts addition
of indoles to α,β-unsaturated enones has been investigated
widely. Recently, a variety of Lewis acids have been used to
promote this reaction, such as Zr(OTf)4 ,[20] NaAuCl4 · 2H2 O,[21]
−
I2 ,[22] SmI3 ,[23] Hf(OTf)4 ,[24] GaI3 ,[25] HfCl4 ,[26] NO+ BF4 [27] and
[28]
Although numerous advances have
aziridin-2-yl methanols.
been achieved, there are still some drawbacks in previous synthetic
methods, such as the need for large amounts of expensive and
toxic metal salts or drastic reaction conditions. Moreover, these
catalysts often do not work when using chalcones as Michael
Appl. Organometal. Chem. 2009, 23, 114–118
H
N
O
Ph
Catalyst
Ph
1a
N
H
2a
O
Ph
Ph
3a
Scheme 1.
acceptors. Therefore, the development of cheaper, simpler and
more efficient catalysts for Friedel–Crafts type reactions of indoles
and chalcones is highly desirable.
Results and Discussion
To establish suitable Friedel–Crafts reaction conditions, we
selected the reation of indole with chalcone as a model (Scheme 1).
First of all, we screened various bimetallic systems in which iron
salts were regarded as center metals, such as Fe–Pd, Fe–In, Fe–Cu,
Fe–Zn and Fe–Ni systems. All the results are listed in Table 1. In the
iron–palladium system, we incidentally found that 84% of desired
product 3a was obtained when 5 mol% of FeCl3 and 5 mol% of
PdCl2 were used as cocatalysts in CH3 OH at room temperature after
∗
Correspondence to: Chun-Gu Xia and Li-Wen Xu, State Key Laboratory for
Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, and Graduate School of the Chinese Academy of
Sciences, Lanzhou, 730000, People’s Republic of China. E-mail: cgxia@lzb.ac.cn;
licpxulw@yahoo.com
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou
Institute of Chemical Physics, Chinese Academy of Sciences, and Graduate
School of the Chinese Academy of Sciences, Lanzhou, 730000, People’s Republic
of China
b Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry
of Education, Hangzhou Normal University, Hangzhou 310012, People’s
Republic of China
c 2008 John Wiley & Sons, Ltd.
Copyright Michael-type Friedel–Crafts reactions of indoles with chalcones
O
HN
H
N
R2
5 mol% FeCl3/5 mol% PdCl2
R1
R3
1a-f
R3
O
15 mol% Acac, CH3OH, r.t.
R1
R2
2a-d
3a-p
Scheme 2.
H
N
O
Table 1. Michael-type Friedel–Crafts reaction of indole with chalcone
promoted by bimetallic catalyst in the absence of any ligand
5 mol% FeCl3/5 mol% PdCl2,
N
H
Entrya
15 mol% Acac,CH3OH,r.t.
O
Isolated yield: 74%
Scheme 3.
Appl. Organometal. Chem. 2009, 23, 114–118
Metal
salt 2
FeCl3
–
PdCl2
FeCl3
FeCl3
Pd(NO3 )2 · 2H2 O
FeCl3
PdCl2 (CH3 CN)2
FeCl3
PdCl2 (CH3 CN)2
–
PdCl2
PdCl2
Fe(NO3 )3 · 9H2 O
FeCl3 · 6H2 O
PdCl2
FeCl3
PdCl2
FeCl3
InCl3
FeCl3
Cu(OTf)2
CuSO4 · 5H2 O
FeCl3
FeCl3
ZnCl2 · 2H2 O
FeCl3
ZnBr2
FeCl3
Zn(OTf)2
FeCl3
Ni(OTf)2
FeCl3
Ni(ClO4 )2
Ni(OAc)2 · 4H2 O
FeCl3
FeCl3
Ni(NO3 )2 · 6H2 O
FeCl3
NiCl2 · 6H2 O
Reaction Yield
Solvent time (h) (%)b
CH3 OH
CH3 OH
CH3 OH
CH3 CN
CH2 Cl2
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
24
24
13
13
24
24
24
24
18
24
18
36
41
41
40
41
41
41
35
40
Trace
84
Trace
NRc
Trace
Trace
39
60
92d
Trace
11
15
13
11
14
11
11
10
43
Trace
a Reaction conditions: 5 mol% of FeCl , 5 mol% of PdCl ,
3
2
0.55 mmol/0.5 mmol of indole/chalcone and 2 ml of solvent at room
temperature for 24 h.
b Isolated yields.
c No reaction.
d The reaction was carried out at 50 ◦ C.
the various solvents tested, CH3 OH was found to be the best
solvent with a yield of 95% (entry 14); moderate yield (59%) was
obtained in ethanol (entry 15). It should be noted that this reaction
could be occur in pure H2 O under similar reaction conditions
(entry 22). We presume that, besides being a solvent, CH3 OH can
provide an acidic environment for the reaction.
To investigate the generality of this method, the reaction of
various indoles and different enones was examined under the
optimized reaction condtions (5mol% of FeCl3 , 5mol% of PdCl2
and 15mol% Acac, 1 equiv. chalcone and 1.1 equiv. indole in CH3 OH
at room temperature; Scheme 2). All of the results are summarized
in Table 3. To sum up, the yields of the products were higher
than those catalyzed by the Fe–Mg–HMPA system. Compared
with previously reported results, the dramatic improvement of
this work is the smaller amount of bimetallic catalysts needed,
half that needed for the Fe–Mg–HMPA catalysts. In general, the
reactions proceeded smoothly with high selectivities for various
indoles 2a–d with enones in moderate to good isolated yields at
room temperature (up to 99%). The process worked noticeably
c 2008 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
115
24 h (Table 1, entry 2), but the reaction did not occur when other
palladium salts were used under the same conditions (entries
3–5). In addition, only trace product was detected with FeCl3
or PdCl2 alone (entries 1 and 6), which showed this bimetallic
catalytic system has a dramatic effect in promoting this reaction.
Subsequently, we obtained the desired product with yields of 39
and 60% by replacing FeCl3 with Fe(NO3 )3 · 9H2 O and FeCl3 · 6H2 O
respectively (entries 7 and 8). The yield could have a remarkable
improvement by increasing the temperature to 50 ◦ C (entry 9).
Therefore, we could conclude that FeCl3 was the most suitable
iron salts for this reaction and iron salts with crystal water could
result in decreased yield. In the iron–copper system, Cu(OTf)2 and
CuSO4 · 5H2 O could only give lower yields of the desired product,
and the reaction did not proceed at all with other copper salts
(entries 11 and 12). Similarly, only poor to moderate yields were
obtained when using Fe–Zn or Fe–Ni as a bimetallic catalytic
system (entries 13–20). All the results indicated that FeCl3 and
PdCl2 were the optimized bimetallic catalysts and there was a
remarkable synergistic effect between them.
In order to further improve the yields of the Friedel–Crafts
product, we reviewed the effect of various additives on the
reaction between indole and chalcone (Table 2). Unexpectedly,
we found that, in the presence of 10 mol% of FeCl3 and 10 mol%
of PdCl2 in CH3 OH at room temperature, the reaction afforded
the desired product 3a in 68% yield when 30 mol% hexamethyl
phosphoric triamide (HMPA) was used as additive (Table 2, entry
1). The reaction became very sluggish when using trans-1,2cyclohexanediamine and triphenyl phosphorous as additives,
which was presumably ascribed to the negative effect of base
additive on the reaction (entries 2 and 3). Considering that it is
difficult to react iron metal with ligands, addition to some protic
reagents could favor the reaction. In the subsequent study, we
were pleased to find that, in the presence of 5 mol% of FeCl3 and
15 mol% of acetylacetone (Acac) at room temperature in CH3 OH
as solvent, the reaction proceeded smoothly to afford product 3a
in 75% yield (entry 4). Encouraged by this result, we carried out the
reaction in the presence of 5 mol% of FeCl3 –PdCl2 and 15 mol%
Acac in CH3 OH at room temperature, and the yield increased to
99% (entry 9). Then we screened some dicarbonyl compounds
as additives. Among various dicarbonyl compounds used for this
transformation, Acac was found to be the most effective one in
terms of yield (entries 9–13). In addition, we investigated the
impact of solvents on the model reaction (entries 14–22). Among
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Metal
salt 1
Y.-H. Gao et al.
gaoyh-1 + 25v
081015-04# 1 (0.210) Sm (Mn, 2x0.30)
100
Scan ES+
4.82e8
340.5
236.3
348.0
356.0
[Chalcone+FeCl3+PdCl2]+
or [FePd(Chalcone)Cl5]+
%
522.5
444.6
542.5
358.0
452.5
544.5
439.6
358.5
264.2
359.0
334.4
507.5
330.4
381.7
545.4
436.6
546.5
715.5
0
250
300
350
400
450
500
550
600
650
700
750
m/z
Figure 1. ESI mass spectrum of the FeCl3 –PdCl2 –chalcone intermediate in MeOH.
116
more efficiently for N-substituted indole 2b with different enones
and the yields of addition products were good to excellent (entries
7–11). Unfortunately, the reaction of 5-Br substituted indole 2d
with chalcone afforded only the desired products in 54% yield
(entry 15). In addition, we found that the electron effect of enones’
substituents had a profound impact on the yields of the reaction.
For the same indole, enones with electron-donating substituents
would give higher yields than those with electron-withdrawing
substituents (entries 8–11), and the trend also applied to indoles.
Interestingly, the enones with ortho-substituents afforded higher
yields than those with para-substituents (entries 10 and 11).
It is reasonable that the ortho-substituted group favored the
interaction of the activated olefin bond with the catalyst, which
increased the reactivity of enone in the Friedel–Crafts reaction of
indole. Almost all reactions are clean and give the C3 -substitution
product exclusively, and the target compounds are obtained in
good yields with no formation of side products such as dimers or
polymers, which are frequently encountered under the influence
of strong protic acids.
In addition, the optimal conditions also was applied for the
cyclic enones. For example, the F–C alkylation product of indole
with cyclohex-2-enone under the optimized reaction condtions
was obtained in 74% yield.
To investigate the mechanism of bimetallic iron and palladiumcatalyzed Michael-type Friedel–Crafts addition of indoles with
chalcones, another catalytic procedure was investigated. FeCl3 ,
PdCl2 and acetylacetone were mixed and stirred for 2 h, then chalcone and indole were added to the catalyst mixture. After 24 h, the
www.interscience.wiley.com/journal/aoc
yield was almost the same as that of the reported procedure (96%
yield). Besides the investigations on the catalysis performances,
we also monitored the intermediate from the Fe–Pd catalyst
and chalcone by ESI-MS, without addition of indole (Fig. 1). The
main peak of the spectrum was characterized as a bimetallic
complex of Fe–Pd with chalcone by HR-ESI-MS (m/z = 544.5):
[FePd(Chalcone)Cl5 ]+ . In addition, we performed IR analysis of the
present bimetallic catalytic system and the expected interaction
was comfirmed by the correspoding spectrum (see Supporting
Information). The mixture of chalcone and PdCl2 resulted in
the appearance of a new peak (1688 cm−1 ) in comparison with
chalcone, and there was almost no difference for the other peak.
Interestingly, the mixture of FeCl3 and chalcone gave a larger difference in the IR spectrum: the diagnostic peaks of chalcone, 1661,
1604 and 1573 cm−1 , were shifted to 1646, 1598 and 1572 cm−1 ,
respectively. Based on the catalytic performance and ESI and IR
spectrum, it is more reasonable that a bimetallic iron and palladium complex was formed and acted as a super Lewis acid in this
Michael-type Friedel–Crafts addition of indoles with chalcones.
Conclusion
In summary, we have demonstrated that iron–palladium–
acetylacetone is a superior bimetallic catalytic system with strong
Lewis acidic activity for the Michael-type Friedel–Crafts reactions
of indoles with chalcones. This catalytic system has the advantages
of mild reaction conditions, smaller amount of metal salts, higher
c 2008 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2009, 23, 114–118
Michael-type Friedel–Crafts reactions of indoles with chalcones
Table 2. Michael-type Friedel–Crafts reaction of indole with chalcone
catalyzed by FeCl3 and PdCl2 under various additives and different
sovlents
Entrya
Metal
salt 1
Metal
salt 2
1
FeCl3
PdCl2
2
FeCl3
PdCl2
3
FeCl3
PdCl2
4
5
6
FeCl3
FeCl3
FeCl3
–
–
–
7
8
9
10
11
12
13
14d
15d
16d
17d
18d
19d
20d
21d
22d
–
–
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
PdCl2
–
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Ligand
Hexamethyl
phosphoric
triamide
trans-1,2-Cyclohexanediamine
Triphenyl
phosphorous
Acetylacetone
Dibenzoylmethane
2-Acetylcyclohexanone
Acetylacetone
Acetylacetone
Acetylacetone
t-Butyl acetoacetate
Diethyl malonate
Ethyl acetoacetate
Benzoylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Solvent
Yield
(%)b
CH3 OH
68c
CH3 OH
Trace
CH3 OH
10
CH3 OH
CH3 OH
CH3 OH
75
80
69
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3 OH
Ethanol
Et2 O
CH2 Cl2
CH3 CN
THF
Toluene
Acetone
H2 O
46
11
99
96
95
97
88
95
59
45
68
26
26
39
66
12
a Reaction conditions: 5 mol% of FeCl , 5 mol% of PdCl and 15 mol%
3
2
of ligand, 0.55 mmol/0.5 mmol of indole/chalcone and 2 ml of Solvent
at room temperature for 24 h.
b Isolated yields.
c 10 mol% of FeCl , 10 mol% of PdCl , and 30 mol% of Ligand.
3
2
d 5 mol% of FeCl , 5 mol% of PdCl , and 10 mol% of ligand.
3
2
yields of desired products and operational simplicity, which makes
it a useful and promising process for the synthesis of indole
derivatives. Further studies to address extension to the asymmetric
process and the comprehension of the reaction mechanism are
currently underway.
Table 3. FeCl3 –PdCl2 –acetylacetone
catalyzed
Friedel–Crafts reactions of indoles with chalcones
Entrya
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Michael-type
R1
R2
R3
Product
Yield (%)b
H
H
p-OCH3
p-OCH3
H
H
H
H
p-OCH3
H
H
H
H
H
H
H
H
p-OCH3
H
p-OCH3
p-Cl
o-Cl
H
p-OCH3
H
p-Cl
o-Cl
H
p-Cl
p-OCH3
H
p-Cl
H
H
H
H
H
H
N-CH3
N-CH3
N-CH3
N-CH3
N-CH3
2-CH3
2-CH3
2-CH3
5-Br
5-Br
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
99
90
93
72
60
77
92
97
98
84
96
87
76
87
54
83
a Reaction conditions: 5 mol% of FeCl , 5 mol% of PdCl and 15 mol%
3
2
of Acac, 0.55 mmol/0.5 mmol of indole/chalcone and 2 ml of CH3 OH at
room temperature for 24 h.
b Isolated yields.
Representative experimental procedure of Michael-type
Friedel–Crafts reaction
FeCl3 (0.025 mmol), PdCl2 (0.025 mmol), and acetylacetone
(0.075 mmol) were added into a solution of enone (0.5 mmol)
and indole (0.55 mmol) in freshly distilled CH3 OH (2 ml). After
stirring at room temperature for 24 h, the mixture was diluted
with H2 O (10 ml) and extracted with EtOAc (3 × 15 ml). The combined organic layers were dried (Na2 SO4 ), concentrated in vacuo
and purified by column chromatography on silica gel (200–300
mesh, gradient eluted with EtOAc–petroleum ether = 1 : 10–1 : 5)
to gain the pure product. All the products are known[16,17] and
structures were confirmed by MS, NMR and IR.
Supporting information
Supporting information may be found in the online version of this
article.
Acknowledgements
Experimental
This study was supported by the National Natural Science Founder
of China (NSFC) for financial support of the work (No. 20572114,
20625308).
General
Appl. Organometal. Chem. 2009, 23, 114–118
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